JPH04330045A - Production of deacetylcolchicine - Google Patents

Abstract

PURPOSE:To readily obtain deacetylcolchicine useful as an intermediate, etc., for anticancer agents and antimicrobial agents from colchicine in a reaction process of one stage in good yield without forming isodeacetylcolchicine as a byproduct by utilizing a Meerwein reagent. CONSTITUTION:Colchicine expressed by formula I is reacted with a Meerwein reagent (especially triethyloxonium fluoroborate) expressed by formula II (R is alkyl) and then simply treated with water to afford deacetylcolchicine expressed by formula III, having carcinostatic action itself and useful also as a synthetic intermediate for colchicine derivatives having excellent carcinostatic actions, antimicrobial actions and other physiological actions. The trialkyloxonium fluoroborate is preferably used in an amount within the range of 1-1.5mol based on 1mol colchicine.

Description

[Detailed description of the invention]

The present invention provides a novel method for producing deacetyl colchicine, which is useful as a synthetic intermediate for colchicine derivatives that have excellent anticancer activity, antibacterial activity, and other physiological activities, and which itself also has anticancer activity. Regarding.

[0002] Deacetylcolchicine (also known as trimethylcolchitic acid methyl ether) is a known compound in itself, and the conventional method for producing it is to hydrolyze colchicine using a mineral acid such as 20-30% sulfuric acid. A method of deacetylation has been adopted. However, in this method, the methyl group of the 7-membered ring is also removed at the same time as the acetyl group is removed to form colchitic acid (another name: trimethylcolchitic acid), so it is necessary to methylate this colchitic acid by allowing diazomethane to act on it. At this time, deacetylcolchicine and its isomer isodeacetylcolchicine are produced as by-products, which leads to a decrease in the yield of deacetylcolchicine, and at the same time, it is more complicated to obtain pure deacetylcolchicine. There are drawbacks such as the need for extensive purification operations [J. Am. Chem. Soc. ,75,5292(
1953)].

[0003] The present inventors have conducted intensive studies on a method for producing deacetylcolchicine easily and in a high yield without the drawbacks of the conventional methods described above, and as a result, they have developed a method using the Meerwein reagent. The inventors have now completed the present invention by discovering that deacetylcolchicine can be easily produced from colchicine in a single reaction process in a high yield without producing isodeacetylcolchicine as a by-product.

Thus, according to the invention, the formula

0005
]

[Chemical formula 3]

A formula characterized in that colchicine represented by: is reacted with trialkyloxonium fluoroborate and then treated with water.

[0007]

[C4]

A method for producing deacetylcolchicine shown below is provided.

The reaction between colchicine and trialkyloxonium fluoroborate is usually carried out using halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, and trichloroethylene; ethyl ether;
aliphatic ethers such as mercellosolve; in an inert organic solvent such as aromatic hydrocarbons such as benzene and toluene at a temperature between about 0°C and about 30°C, preferably between about 0°C and
It can be carried out at about room temperature.

The trialkyloxonium fluoroborate reacted with colchicine has the following formula:

[0011]

[Chemical formula 5] (R)3O+・BF4− (III
), where R represents an alkyl group, specifically, triethyloxonium fluoroborate [(C2H
5) 3O+.BF4-] is suitable.

[0012] The above trialkyloxonium fluoroborate is generally used in an amount of 1 to 2 mol per mol of colchicine.
Preferably, it can be used within the range of 1 to 1.5 mol.

By the reaction of colchicine and trialkyloxonium fluoroborate, the following formula

[0014]

[C6]

It is presumed that a compound represented by the following formula, where R is as defined above, is produced.

Deacetylcolchicine of formula (II) can be obtained by directly treating the resulting compound of formula (IV) with water. Treatment with water is typically carried out at temperatures between about 0° and about 30°C, particularly at room temperature.
This can be carried out by stirring for about minutes to 3 hours. Water can be used in an amount of at least 1 mole, usually in large excess, per mole of colchicine used as starting material.

[0017] As a result, deacetylcholine is produced in a state dissolved in the aqueous layer, which can be separated from the aqueous layer and produced by a method known per se. For example, an alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium hydrogen carbonate is added to the aqueous layer to bring the pH to about 9.
After making it alkaline within the range of ~10, halogenated hydrocarbons such as methylene oxide, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene; aliphatic ethers such as ethyl ether and methyl cellosolve; aromatic ethers such as benzene and toluene. Deacetylcolchicine can be separated by extraction using an organic solvent such as a hydrocarbon.

The diacetylcolchicine thus separated can be further purified by converting it into a salt such as tartrate or malate.

Next, the method of the present invention will be explained in more detail with reference to Examples.

[0020]

[Example 1] Colchicine (4.00g, 10mmol)
was dissolved in dry methylene chloride, cooled to 0°C, and triethyloxonium fluoroborate (Meerwein reagent) was added.
A methylene chloride solution (15 mmol) of the mixture was added dropwise. 0℃
After stirring for 1 hour at room temperature, the mixture is further stirred for 5 hours. Add 30 ml of water to the reaction mixture and stir for 1 hour. After stirring, separate the aqueous layer using a separatory funnel. The methylene chloride layer is further extracted five times with 50 ml of water. The methylene chloride layer is dried with magnesium sulfate and used to recover colchicine.

[0021] The aqueous layer was adjusted to pH using 1N sodium hydroxide.
10 and extracted with chloroform. After drying the chloroform layer with magnesium sulfate, it is concentrated using an evaporator. Add 30 ml of ethanol to the residue and dissolve it, D
- Add 1 g of tartaric acid and heat for 1 hour. The precipitate formed after cooling to room temperature is filtered. The obtained tartrate is dried using a desiccator (decomposed at mp 219-220°C).

Dissolve tartrate in 50 ml of water and add 1N
The pH is adjusted to 10 again with sodium hydroxide and extracted with chloroform. After drying with magnesium sulfate, oily deacetylcolchicine is obtained by vacuum concentration using an evaporator. 1.38g, yield 39%.

[0023] By using silica gel column chromatography on the first methylene chloride layer, unreacted colchicine can be recovered from the benzene-acetone solvent outflow portion (1.71 g). When this is subtracted, the yield of the above deacetylcolchicine becomes 61%.

Claims (1)

[Claims] [Claim 1] Deacetylcolichine represented by the formula [Chemical formula 2], which is obtained by reacting colchicine represented by the formula [Chemical formula 1] with trialkyloxonium fluoroborate and then treating with water. Production method.